SIGNAL TRANSDUCTION RESEARCH PROGRAM PROGRAM CODE: ST PROJECT SUMMARY/ABSTRACT The Signal Transduction (ST) Research Program harnesses research talent across YCC to understand fundamentals of key pathways that drive carcinogenesis and cancer progression, with the goal of enabling development and improvement of effective targeted cancer therapeutics. The ST Program was established in 2005 with two major premises. First, most human cancers are driven by dysregulation of cellular pathways that normally link growth factor-dependent signaling to cellular processes relevant to cancer, including regulation of cell division, protection from apoptosis, tumor angiogenesis, lineage restrictions, and cancer progression. Second, molecules involved in signal transduction networks ? including growth factors, receptor kinases, non- receptor kinases, and components that they regulate ? have emerged as important targets for cancer therapies. The portfolio of effective FDA-approved cancer therapies that attack oncogenic signaling proteins is extensive, and now includes third-generation agents that have been refined based on clinical experience. New categories of agents, including PARP inhibitors and CDK inhibitors, have more recently been shown to be effective and are now in routine clinical practice. Immunotherapy has transformed the cancer treatment landscape; nonetheless, current checkpoint inhibitors benefit only a minority of patients ? creating an urgent need to define relevant signaling pathways that can be targeted alongside checkpoint blockade to overcome both primary and acquired resistance. Challenges remain for all signaling-targeted therapies, including intrinsic and treatment-selected resistance and failure to successfully target RAS. ST takes full advantage of cutting- edge technologies to identify critical drivers of initiation and progression of human cancers, as well as their response to therapy ? bringing together leading investigators across the spectrum of cancer research to advance fundamental understanding of cancer signaling and overcome treatment challenges. The Program leverages a variety of mechanisms to build new initiatives and research areas, including focused research meetings, pilot funding, member education, and matchmaking collaborations. The 38 ST program members come from 12 departments in 3 Schools. Members investigate all aspects of signal transduction research related to cancer, including receptor signaling mechanisms, signaling pathways, cytoskeleton, cell polarity, intracellular protein trafficking, and integrated signaling networks. Recruitment of 10 new faculty with research programs centered on cancer signaling and translation, and pruning of less cancer-oriented faculty has increased cancer focus. Since the last CCSG cycle, ST members published 546 (July 1, 2012 - June 1, 2017) cancer-related papers (11% intra-programmatic, and 32% inter-programmatic). Total ST cancer research funding is $15.8M (direct), of which $9.3M is peer-reviewed, and $3.9M NCI-funded. This represents a more than 2-fold increase in overall funding, an 80% increase in peer-reviewed funding and a 71% increase in NCI funding relative to the last submission in 2012. !